Malnutrition in HIV-Infected Children Is an Indicator of Severe Disease with an Impaired Response to Antiretroviral Therapy.

Michelle Q Phan,Chirjeev Kindra,Thumbi Ndung'U,Maximilian Muenchhoff,Michael Healy,Alejandro Palma,Henrik Kloverpris,Philip Goulder,Philip Larussa,Andreas Groll,Julia Roider,Magdalena E Sobieszczyk,Angeline Moonsamy,Ravesh Singh,Alasdair Leslie,Mohendran Archary,Callum Mcgregor,Thobekile Sibaya,Raziya Bobat

doi:10.1089/aid.2016.0261

Abstract

This observational study aimed to describe immunopathogenesis and treatment outcomes in children with and without severe acute malnutrition (SAM) and HIV-infection. We studied markers of microbial translocation (16sDNA), intestinal damage (iFABP), monocyte activation (sCD14), T-cell activation (CD38, HLA-DR) and immune exhaustion (PD1) in 32 HIV-infected children with and 41 HIV-infected children without SAM prior to initiation of antiretroviral therapy (ART) and cross-sectionally compared these children to 15 HIV-uninfected children with and 19 HIV-uninfected children without SAM. We then prospectively measured these markers and correlated them to treatment outcomes in the HIV-infected children at 48 weeks following initiation of ART. Plasma levels of 16sDNA, iFABP and sCD14 were measured by quantitative real time PCR, ELISA and Luminex, respectively. T cell phenotype markers were measured by flow cytometry. Multiple regression analysis was performed using generalized linear models (GLMs) and the least absolute shrinkage and selection operator (LASSO) approach for variable selection. Microbial translocation, T cell activation and exhaustion were increased in HIV-uninfected children with SAM compared to HIV-uninfected children without SAM. In HIV-infected children microbial translocation, immune activation, and exhaustion was strongly increased but did not differ by SAM-status. SAM was associated with increased mortality rates early after ART initiation. Malnutrition, age, microbial translocation, monocyte, and CD8 T cell activation were independently associated with decreased rates of CD4% immune recovery after 48 weeks of ART. SAM is associated with increased microbial translocation, immune activation, and immune exhaustion in HIV-uninfected children and with worse prognosis and impaired immune recovery in HIV-infected children on ART.

Highlights

Malnutrition was estimated to be the underlying cause for 45% of deaths in children less than 5 years of age in 2011 globally.[1]
severe acute malnutrition (SAM) is associated with increased microbial translocation, immune activation, and immune exhaustion in HIV-uninfected children and with worse prognosis and impaired immune recovery in HIV-infected children on antiretroviral therapy (ART)
In HIV-infected children, it is not known whether SAM is associated with increased microbial translocation, immune activation, and immune exhaustion and whether this is modulated by ART

Summary

Introduction

Malnutrition was estimated to be the underlying cause for 45% of deaths in children less than 5 years of age in 2011 globally.[1] The prevalence of malnutrition in HIVinfected children is as high as 40%, making clinical management of this vulnerable population even more challenging.[2,3] Co-occurrence of severe acute malnutrition (SAM) and HIV results in increased morbidity and mortality largely due to increased incidence and severity of concurrent infections.[4,5,6] Immunological alterations such as systemic inflammation and impaired cellular immune responses have been attributed to malnutrition[7] that could explain this increased susceptibility to infection especially when exacerbated by HIV infection, but the underlying mechanisms remain largely unresolved. In HIV infection breakdown of the intestinal barrier, depletion of gut-resident CD4+ T cell populations and mucosal immune dysregulation results in microbial translocation that drives systemic immune activation.[13] Chronic immune activation is a hallmark of disease progression in HIV-infected children and results in accelerated loss of CD4 T cells, immune dysregulation, and immune exhaustion.[14]

Methods

Results

Conclusion